Christini Fund
The Metabolic Features of Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS) Robert K. Naviaux, MD, PhD Professor of Genetics, Medicine, Pediatrics, and Pathology Co-Director, The Mitochondrial and Metabolic Disease Center University of California, San Diego School of Medicine Talk for the Centers for Disease Control SEC Program Coordinated by Dr. Elizabeth Unger and Dr. Dana Brimmer May 25, 2017
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Outline • What is the Cell Danger Response (CDR)? • Metabolic reflexes and the healing cycle • Purinergic Sensory processing receptors needed for cell danger and safety detection • Metabolic lessons from the Antiviral response • Metabolic features of ME/CFS • Metabolic features of Dauer Exit—clues for treatment
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Mitochondria are the Cell’s “Canaries in the Coal Mine”
= Their Metabolism is so Fast, They are the First to Sense Danger or Toxicity
+ Danger
Regulators of cell oxygen Regulators of Cell Defense And Innate Immunity Cellular Power Plants Regulators of 500 Reactions in Metabolism
Universal Alarm Signals Trigger the Cell Danger Response
Self-defense is Nature’s oldest law. John Dryden (1681)
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What is the Cell Danger Response (CDR)? An Archetypal Stress: a Viral infection
The CDR is a Coordinated, Multisystem, “Metabolic Reflex” Caused by an Electron Steal
Capillary
Decrease oxygen consumption increase dissolved O2 concentration O2 1. Shift from polymer to monomer O2 synthesis (DG; FA, AA, Dipeptides, NTs) 2. Stiffen cell membranes, lipid rafts O2 3. Release anti-viral and anti-microbial chemicals O2 4. Increase mitochondrial fission and autophagy & unfolded protein response 5. Change DNA and histone methylation— chromatin structure 6. Mobilize endogenous retroviruses, LINEs, and SVAs 7. Warn neighboring cells and call in effector cells—the “purinergic halo” 8. Alter host behavior to prevent spread of disease to kin 4 From Naviaux RK. Metabolic Features of the Cell Danger Response. Mitochondrion, 2014. 0.
Starting the CDR is Universal with Every Stress or Threat Mitochondria sense and respond to changes in the cellular environment.
UDP-Gal UTP ATP UDP ADP
ATP
ATP Pannexin /P2X7
ADP AMP ATP CD73
Ectonucleotidases
Mitochondria
ATP and Other Agonists
UTP A
Suramin and Other Antagonists
UTP GTP
CD39
Ado
ATP
ATP
Dissipative eATP Loss Antipurinergic Therapy (APT)
P2X and P2Y Receptors
ADP ATP ADP
A
Short Path Retrograde
ATP
U G
Ectonucleotidases
Mitochondria
ATP and Other Agonists
P2X and P2Y Receptors
dNTPs
ATP
DNA
ATP
ATP
P2X and P2Y Receptors
dNTPs
DNA
Unstirred water layer
ATP
Chemical Gradient of Extracellular Nucleotides
Paracrine Signaling to Neighboring Cells
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How do cells “smell” safety and danger in the world? (Hint: It’s all about metabolism.) Vertebrate Chemosensory Receptor Evolution Formyl-Peptides
7 Transmembrane GPCRs Sight
Smell
Pheremones
Taste
Chemokines ATP, UTP SCFAs LPAs Nicotine Bradykinin
6 Liman ER. Adv Exp Med Biol, 2012. PMID 22399404
Shi/Zhang. Results Probl Cell Diff, 2009. PMID 19145414
Q: What causes chronic disease? H: Failure to to complete the healing cycle.
Mitochondria
Health and Fitness
Healing
Chronic Disease (30% of Children in US) 7
The Healing Cycle and its Regulation Healing
CDR Stages
Health
Antipurinergic Therapy (APT, eg Suramin)
Injury and Chronic Diseases
Dangers & Stress Injury, infection, trauma, toxins, Radiation, pollution, solvents, Mutagens, heavy/trace metals, Food chain degradation, ecosystem disruption
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Fatigue in ME/CFS • Fatigue is the result of two main factors: – Dissipative losses of ATP through channels in the cell membrane, and – Reallocation of cellular resources away from mitochondrial energy production (oxphos) • This is the result of mitochondria following “new orders” from the nucleus, ie, “regulated mitochondrial dysfunction” • This is not from an intrinsic “defect” in mitochondria themselves or a specific genetic mutation, ie, recovery is possible
• “It takes more energy to relax than to react.” – Anxiety, restlessness, irritability, fear of change, OCD behaviors, sensory & chemical hypersensitivities, meltdowns, and bouts of hyperactivity, and even seizures, are hallmarks of a low energy state 9
Metabolomics—A Drop of Blood is Like a Sample of Water from a River or Ocean Ecosystem
LC-MS/MS
Chemical Basis of Health and Disease 10
Metabolomics Permits Diagnosis of ME/CFS A
B
Male Chronic Fatigue Syndrome
Control
Female
Chronic Fatigue Syndrome
Naviaux, et al. Metabolic features of chronic fatigue syndrome. PNAS 113: E5472, 2016.
Control
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Pathway Abnormalities—Defining the Metabolic Reflex of the CDR The CDR Chronic Fatigue Syndrome • Sphingolipids • Phospholipids • Sterols/Cholesterol • Purines • Methionine/Cysteine • Propionate • Krebs cycle • Folate/B12 • Ascorbate Naviaux, et al. Metabolic features of chronic Fatigue syndrome. PNAS 113: E5472, 2016. Gender-selective responses noted.
Post-Zostavax Vaccination1 • Krebs cycle • Purines • Sphingolipids • Sterols/Cholesterol • Methionine/Cysteine • Propionate • Inositol lipids • Porphyrin/Heme/Glycine • Amino/Sialic acid sugars Li, et al. Metabolic phenotypes of response to Vaccination in humans. Cell 169:862, 2017. 1PBMC transcription and metabolism. Mixed male and female responses.
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Metabolic Pathway Abnormalities in Males and Females with ME/CFS Male
Female
Serine/1-Carbon Metabolism SAM, SAH, Met Very Long Chain FAO Propiogenic AA Threonine
50% Shared
Fatty Acid Oxidation Vitamin C/Collagen Bile acids Endocannabinoids Vitamin B12 Amino Sugars
Sphingolipids Phospholipids Glycosphingolipids Purines Microbiome Cholesterol Vitamin B2 (Riboflavin) P5C, Arginine, Proline Branch Chain AA
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ROC Curve Accuracy Analysis— Metabolomic Diagnosis of ME/CFS A
B
Males AUC = 0.94 95% CI: 0.84-1.0
Females AUC = 0.96 95% CI: 0.86-1.0
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Hypometabolic Persistence and Survival States in Nature • Persister Cells – Lyme – Tuberculosis
• • • • • • •
Embryonic Diapause Hibernation Torpor Estivation Tun Dauer Caloric restriction/Longevity research
A B
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Reproductive Cycle = 3 days Menopause After 6 days Normal life span = 14 days
C. elegans
Normal
Dauer Lipid Droplets Dauer Shifts • • • • • •
Lipid Droplets
Stop eating caloric restriction Mitochondrial oxphos declines Oxygen consumption declines Lipid droplets accumulate Glycolysis increases Glyoxylate shunt increases to increase OAA and gluconeogenesis
www.wormatlas.org
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Metabolic Changes Associated with Recovery/Exit from Dauer L1
Stress
Adults
Early dauer (3-4days)
Late dauer (10 weeks)
Recovery
20x 17
Choreographed Metabolic Features of Dauer Exit
The sequence (timing) of changes is important
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8
6
PYRUVIC ACID 15
PIPECOLIC ACID 20
15
GUANOSINE 25
UREA
20
ve ry
0 ve ry
Fold Change
10
20 hr _R ec o
0 15
ve ry
0 2
GLYCEROL
10 hr _R ec o
DR Late 25
2h r_ R ec o
DR Early NADPH
D au er
D 6
au er 2h r_ R ec ov er y 10 hr _R ec ov er y 20 hr _R ec ov er y
NAD+
D
10 4
Fold Change
L4
au er 2h r_ R ec ov er y 10 hr _R ec ov er y 20 hr _R ec ov er y
20
Fold Change
30
D
au er 2h r_ R ec ov er y 10 hr _R ec ov er y 20 hr _R ec ov er y
D
Fold Change
Dauer Exit—
Clues for CFS Treatment
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CITRULLINE
20 4
5
2
0
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Treatment Strategy for ME/CFS • Remove the CDR trigger if it is still present • Refill the metabolic tank—raw materials for exit from winter and return to“spring and summer metabolism” – Normalize calorie intake and nutrition • Restore depleted metabolic reserves as guided by metabolomics
• Use antipurinergic therapy (APT), e.g., low-dose suramin, to reprogram metabolism and to progress through the healing cycle – Pilot study of low-dose suramin in CFS is seeking funding to launch later this year. – See: http://naviauxlab.ucsd.edu/support/
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Research Support • • • • • • • • • • •
Dan Wright Family Foundation The UCSD Christini Fund Autism Research Institute The Gupta Family and Satya Fund N of One: Autism Research Foundation Christine Shimizu The Rodakis Family 1996-1998 Lennox Foundation The UCSD Mito Walk n’ Roll 5K It Takes Guts Foundation Jane Botsford Johnson Foundation (the essential preclincal studies) Open Medicine Foundation (OMF)
Thank You
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